1. Field of the Invention
This invention relates to a novel group of ansa macrolide compounds which have utility, inter alia, as chemotherapeutic agents for the remission of malignancies in animals.
2. Description of the Prior Art
The isolation of three ansa macrolides from ethanolic extracts of Maytenus ovatus and Maytenus buchanii was first reported by S. M. Kupchan et al. and is the subject of U.S. Pat. No. 3,896,111. These maytanside esters are characterized by the structural formula ##STR2## and include maytansine in which R=CH.sub.3, maytanprine in which R=CH.sub.2 CH.sub.3, and maytanbutine in which R=CH(CH.sub.3).sub.2. Kupchan reports that these compounds showed activity against lymphocytic leukemia P388 when administered at a level in the range of 20 to 100 micrograms/kg. of body weight. Two analogs of maytanbutine isolated from Colubrina texensis are taught by Wani et al. [J.C.S. Chem. Commun. page 390 (1973)] in which the C-15 position bears either an hydroxyl (colubrinol) or an acetate (colubrinol acetate) side chain. These compounds have also demonstrated activity against lymphocytic leukemia P388 at the microgram per kilogram level, and in addition show cytotoxicity (ED.sub.50) against KB cell culture at 10.sup.-4 -10.sup.-5 .mu.g./ml. In a later publication by Kupchan et al. [J. Org. Chem. 42: 2349-57 (1977)] a variety of maytansinoids are reviewed and are categorized as either maytanside esters (those having a C-3 ester side chain) or as maytansides (those lacking the C-3 ester side chain). Of particular significance is the disclosure of finding yet another antileukemic principle, maytanbutacine. This maytanside ester was isolated from Maytenus serrata and is similar to colubrinol acetate in that it has an acetate side chain in the C-15 position. The difference lies in the C-3 ester group, which is ##STR3## This reference also teaches the isolation of maytansine and related compounds from another celastraceous plant, Putterlickia verrucosa.
The significance ascribed to the various structural entities of the maytansinoids for antileukemic activity is discussed by Kupchan et al. [J. Med. Chem. 21: 31-37 (1978)]. Most important for activity is the presence of a C-3 ester, and the particular structure of the ester is also an influencing factor. The C-9 carbinolamide moiety is shown to be critical for optimal activity. In Table II of this publication, the ED.sub.50 level against KB cell culture of the previously mentioned maytansinoids is shown to be in the range of 10.sup.-5 -10.sup.-7 .mu.g./kg.
Higashide et al. [Nature 270: 721-722 (1977) and U.S. Pat. No. 4,225,494] and Asai et al. [Tetrahedron 35: 1079-85 (1979)] first reported the isolation of ansamitocins, a group of ansamycin antibiotics, from a fermentation broth of Nocardia sp. No. C-15003 (N-1). The structures of these compounds are similar to maytansine, differing only with respect to the C-3 moiety. Ansamitocin demonstrated strong growth inhibitory activities against certain phytopathogenic fungi, dermatophytes, and certain protozoa. Two of the compounds also possess antitumor activity against the P388 strain at doses as low as 0.8-25 .mu.g./kg. body weight, as well as significant activity against B16 melanoma, sarcoma 180, Ehrlich carcinoma, and P815 mastocytoma. Some activity was also shown against leukemia L1210.
In U.S. Pat. No. 4,313,946, Powell et al. disclosed the isolation from Trewia nudiflora L. of a class of maytansinoids characterized by a methoxy group on the C-15 carbon. The compounds included trewiasine, dehydrotrewiasine, and 3'-N-demethyltrewiasine, with at least the former two demonstrating activity in the PS system at 4 .mu.g./kg. dosage level. Also, trewiasine was shown by Freedman et al. (U.S. Pat. No. 4,315,929) as being effective in controlling the European corn borer.